Project Summary/Abstract Chemotherapy-induced peripheral neuropathy (CIPN) can cause persistent pain, numbness, and weakness, which diminish the quality of life in a substantial proportion of cancer patients. Therapies for [painful] CIPN are not effective. Therefore, strategies for treatment and prevention are generally limited to dose delays and dose reductions, which may ultimately impact patient survival. Exactly how chemotherapy-induced nerve damage leads to pain is not well understood. In animal and human studies, chemotherapy causes damage to small diameter nerve fibers located superficially in the skin that transmit nociceptive (pain) information. Loss of these fibers leads to reduced pain sensitivity, rather than pain, suggesting fiber loss alone is not sufficient to explain the development of neuropathic pain. A subset of small diameter nerve fibers, the C mechano-insensitive fibers (CMi) are located deeper in the skin and appear to be spared from direct chemotherapy-induced toxicity. CMi fibers are activated by noxious heat and chemicals and, subsequently, release chemokines that cause vasodilation. In CIPN patients, CMi fibers are sensitized and have abnormally high spontaneous activity. These characteristics suggest CMi fibers play a critical role in generating pain in CIPN and sensitize surrounding fibers. The correct measurement of function of different subtypes of small diameter fibers is critical for patient evaluation, prediction of CIPN development, and personalized treatment tailoring. Conventional noninvasive testing strategies, such as the CO2 laser or contact thermode, cannot safely penetrate the skin to the depth required for reliable stimulation to test epidermal and dermal nociceptive fibers and selectively activate small diameter (C or A?) fibers. This limits the ability to study patients in a clinical setting. As a result, no medical insurances reimburse these tests after three decades of intensive clinical research. In contrast, the newly developed and patented Diode Laser fiber types Selective Stimulator (DLss) can be used at the bedside for diagnostics of CIPN based on the safe and selective stimulation of A? and C (including CMi) fibers in superficial and deep skin. DLss allows for safe noninvasive examination of patients. Preliminary data using the DLss suggests that it can track painful CIPN-induced changes in patients by DLss-evoked pain thresholds. In fact, CIPN patients had significantly higher pain thresholds in superficial A? fibers and slight changes in C-fiber thresholds compared to healthy volunteers, leading to an increased A?:C pain threshold ratio. Based on a clinically proven model of DLss, we will test, in ovarian cancer patients who developed painful CIPN while receiving a [first line treatment:] taxane combined with platinum, if DLss shows a consistently elevated induced A?:C pain threshold ratio and if the A?:C ratio measures the severity and [identifies patients at risk of] developing [painful] CIPN. Aim 1 will establish the relationship between pain and the increase of A?:C pain threshold ratio [in patients with painful CIPN]. It will also quantify the A?:C pain threshold ratio in patients who have developed painless CIPN. Aim 2 will define how the A?:C pain threshold ratio can [identify the progression] of CIPN and correlate A?:C pain threshold change over time with the long-term development of persistent painful or painless neuropathy, or resolution of symptoms and thus identify patients at risk of developing painful CIPN. The proposed feasibility study will test the utility of DLss to quantify CIPN, allowing for a unique ability to detect, evaluate, and predict [the progression of] small fiber neuropathies in the clinic, where currently available tests and diagnostic have failed. Therefore, this allows phase II of the project for optimizing DLss tools and clinical methods and to collect sufficient statistical data for 510K FDA application. Current annual market niche is about $2 million for the tools and services of clinical evaluation of analgesics and investigation of mechanisms of small diameter fibers peripheral neuropathies. The estimated annual market of DLss for application in clinic after it becomes accepted as a reimbursed procedure is over $9 million.